Metabolomic Analysis of Pediatric Patients with Idiosyncratic Drug-Induced Liver Injury According to the Updated RUCAM

Hepatotoxicity, a common adverse drug effect, has been extensively studied in adult patients. However, it is equally important to investigate this condition in pediatric patients to develop personalized treatment strategies for children. This study aimed to identify plasma biomarkers that characterize hepatotoxicity in pediatric patients through an observational case–control study. Metabolomic analysis was conducted on 55 pediatric patients with xenobiotic liver toxicity and 88 healthy controls. The results revealed clear differences between the two groups. Several metabolites, including hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine, glycocholic acid, and taurocholic acid, were identified as potential biomarkers (area under the curve: 0.817; 95% confidence interval: 0.696–0.913). Pathway analysis indicated involvement of primary bile acid biosynthesis and the metabolism of taurine and hypotaurine (p < 0.05). The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity. The accumulation of cytotoxic bile acids should be further investigated to elucidate the role of these metabolites in drug-induced liver injuryInstitute of Health Carlos III grants (PI17/01989) and Servicio Andaluz de Salud (F2-0071-2015

Seroprevalence and epidemiology of hepatitis B and C viruses in pregnant women in Spain. Risk factors for vertical transmission

Background & aim Worldwide, measures are being implemented to eradicate hepatitis B (HBV) and C (HCV) viruses, which can be transmitted from the mother during childbirth. This study aims to determine the prevalence of HBV and HCV in pregnant women in Spain, focusing on country of origin, epidemiological factors and risk of vertical transmission (VT). Methodology Multicentre open-cohort study performed during 2015. HBV prevalence was determined in 21870 pregnant women and HCV prevalence in 7659 pregnant women. Epidemiological and risk factors for VT were analysed in positive women and differences between HBV and HCV cases were studied. Results HBV prevalence was 0.42% (91/21870) and HCV prevalence was 0.26% (20/7659). Of the women with HBV, 65.7% (44/67) were migrants. The HBV transmission route to the mother was unknown in 40.3% of cases (27/67) and VT in 31.3% (21/67). Among risk factors for VT, 67.7% (42/62) of the women had viraemia and 14.5% (9/62) tested HBeAg-positive. All of the neonates born to HBV-positive mothers received immunoprophylaxis, and none contracted infection by VT. In 80% (16/20) of the women with HCV, the transmission route was parenteral, and nine were intravenous drug users. Viraemia was present in 40% (8/20) of the women and 10% (2/20) were HIV-coinfected. No children were infected. Women with HCV were less likely than women with HBV to breastfeed their child (65% vs. 86%). Conclusions The prevalences obtained in our study of pregnant women are lower than those previously documented for the general population. Among the women with HBV, the majority were migrants and had a maternal family history of infection, while among those with HCV, the most common factor was intravenous drug use. Despite the risk factors observed for VT, none of the children were infected. Proper immunoprophylaxis is essential to prevent VT in children born to HBV-positive women.This study received financial assistance from the following: Ciberehd, Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III. ISCIII, Proyecto del Plan Nacional I+D+i 2013-2016 (PI13/01925), Confinanciacio´n Fondos FEDER. Gilead Fellowship Program (GLD14-00292 and GLD15-00307)

Killer immunoglobulin-like receptor and cancer

Introducción: Las células natural killer (NK) juegan un papel importante en la defensa contra las células tumorales. El desarrollo y la función de las células NK se rige por un equilibrio dinámico entre la inhibición y la activación de los receptores de la superficie celular, incluidos los receptores KIR. Pacientes y método: se realiza un estudio de casos y controles que compara a un grupo de 46 ni˜nos diagnosticados de enfermedades malignas, el grupo control está constituido por 82 ni˜nos sanos. Se determinaron y compararon entre grupos los genes, haplotipos y ligandos KIRs. Resultados: no existen diferencias en genes KIRs, haplotipos KIRs ni en ligandos de genes KIRs entre grupos. Sin embargo, al estudiar conjuntamente KIRs y ligandos, k2DS1 C2 fue significativamente superior en el grupo de ni˜nos oncológicos (p◦=◦0,016). Conclusiones: Nuestros resultados no proporcionan evidencia de una asociación entre enfermedades oncológicas pediátricas con genotipos y grupos de genes KIRs. El genotipo k2DS1 C2 podría predisponer a la susceptibilidad a procesos malignos en la población infantil.Introduction: Natural killer (NK) cells play an important role in defense against tumor cells. The development and function of NK cells is governed by a dynamic balance between inhibition and activation of cell surface receptors, including KIR receptors. Patients and method: A case-control study is carried out that compares a group of 46 childrendiagnosed with malignant diseases, the control group is made up of 82 healthy children. KIRsgenes, haplotypes and ligands were determined and compared between groups.Results: There are no differences in KIRs genes, KIRs haplotypes or in KIRs gene ligands betweengroups. However, when KIRS and ligands were jointly studied, k2DS1 C2 was significantly higherin the group of cancer children (p◦=◦0.016).Conclusions: Our results do not provide evidence of an association between pediatric cancerdisease with genotypes and groups of genes KIRs. The k2DS1 C2 genotype could predispose tosusceptibility to malignant processes in children.Instituto de Salud Carlos III - FEDER (números decontrato:PI12 / 00378, SAS-PI-0239/2012, AC-0073-2013

Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children.

La transmisión vertical del virus de la hepatitis C (HCV-VT) es una ruta principal de infección por HCV en niños, pero los factores de riesgo no se comprenden completamente. Este estudio analizó el papel de la interleucina 28B (IL28B) en HCV-VT y en la eliminación espontánea de HCV entre los infantes infectados. Entre 1991 y 2009, se reclutaron 145 madres para este estudio: 100 eran HCV-RNA+ve / VIH negativo (HIV-ve), con 128 niños, y 33 eran HCV-RNA-ve / HCV anticuerpo+ve, con 43 niños. Los infantes fueron evaluados para HCV-RNA al nacer y a intervalos regulares hasta la edad de 6 años. Se determinó IL28B (polimorfismo de nucleótido simple rs12979860) en las madres y los niños. Se asumió HCV-VT cuando los niños presentaron HCV-RNA+ve en dos muestras de sangre consecutivas. Los infantes infectados por HCV-VT se categorizaron como: (1) viremia transitoria con posterior HCV-RNA-ve y sin seroconversión; (2) infección persistente con seroconversión. De las 31 madres con polimorfismo CC, 19 (61%) eran HCV-RNA+ve, mientras que entre las 68 madres con polimorfismo no-CC, 56 (82%) eran HCV-RNA+ve. En total, 26 de 128 (20%) infantes nacidos de madres HCV-RNA+ve adquirieron la infección por HCV, pero solo 9 (7%) estaban crónicamente infectados. La tasa de HCV-VT fue mayor entre las madres con mayor viremia de HCV. No se detectó HCV-VT en las mujeres HCV-RNA-ve. Ni el estado de IL-28 de las madres ni el de los niños se asoció con un mayor riesgo de HCV-VT. Los factores que influyen en la eliminación viral entre los niños infectados fueron el genotipo no-1 y el genotipo CC de IL28B. En la regresión logística, el polimorfismo CC del niño fue el único predictor de la eliminación de HCV en el genotipo-1 de HCV. Conclusión: La alta carga viral materna es el único factor predictivo de HCV-VT. IL28B no juega ningún papel en HCV-VT, pero el polimorfismo CC de IL28B en niños se asocia independientemente con la eliminación espontánea del genotipo-1 de HCV entre los niños infectados. (HEPATOLOGÍA 2011;53:1830-1838

High-resolution hepatitis C virus subtyping using NS5B deep sequencing and phylogeny, an alternative to current methods

HepatitisCvirus(HCV)is classified into seven major genotypesand67 subtypes. Recent studies haveshownthat inHCVgenotype 1-infected patients, response rates to regimens containingdirect-acting antivirals(DAAs)are subtype dependent. Currently available genotypingmethods have limited subtyping accuracy.Wehave evaluated theperformanceof adeep-sequencing-basedHCVsubtyping assay, developed for the 454/GS-Junior platform, in comparisonwith thoseof two commercial assays (VersantHCVgenotype 2.0andAbbott Real-timeHCVGenotype II)andusingdirectNS5Bsequencing as a gold standard (direct sequencing), in 114 clinical specimenspreviously tested by first-generation hybridization assay (82 genotype 1and32 with uninterpretable results). Phylogenetic analysis of deep-sequencing reads matched subtype 1 callingbypopulation Sanger sequencing(69%1b,31%1a) in 81 specimensandidentified amixed-subtype infection (1b/3a/1a) in one sample. Similarly,amongthe 32previously indeterminate specimens, identical genotypeandsubtype results were obtained by directanddeep sequencing in all but four samples with dual infection. In contrast, both VersantHCVGenotype 2.0andAbbott Real-timeHCVGenotype II failed subtype 1 calling in 13 (16%) samples eachandwere unable to identify theHCVgenotype and/or subtype inmore than half of the nongenotype 1 samples.Weconcluded that deep sequencing ismore efficient forHCVsubtyping than currently available methodsandallows qualitative identificationofmixed infectionsandmay bemorehelpfulwith respect to informing treatment strategies withnewDAA-containing regimens across allHCVsubtypesThis study has been supported by CDTI (Centro para el Desarrollo Tecnológico Industrial), Spanish Ministry of Economics and Competitiveness (MINECO), IDI-20110115; MINECO projects SAF 2009-10403; and also by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS) projects PI10/01505, PI12/01893, and PI13/00456. CIBERehd is funded by the Instituto de Salud Carlos III, Madrid, Spain. Work at CBMSO was supported by grant MINECO-BFU2011-23604, FIPSE, and Fundación Ramón Areces. X. Forns received unrestricted grant support from Roche and has acted as advisor for MSD, Gilead, and Abbvie. M. Alvarez-Tejado, J. Gregori, and J. M. Muñoz work in Roche Diagnostic

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

The relation between activator and inhibitor killer-cell immunoglobulin-like receptors and hepatotoxicity in oncological treatment

ANTECEDENTES: Las interacciones moleculares entre los receptores tipo inmunoglobulina de células asesinas (KIRs) y sus ligandos relacionados de clase I del HLA juegan un papel central en la regulación de las respuestas de las células asesinas naturales (NK). El objetivo de nuestro estudio fue determinar el papel que juegan los genes KIR y sus ligandos HLA en la predisposición genética para el desarrollo de hepatotoxicidad en niños tratados con quimioterapia para un proceso oncológico. MÉTODOS: El grupo de estudio estuvo compuesto por 22 niños con cáncer, siendo tratados con quimioterapia en la Unidad de Oncología Pediátrica del Hospital Maternidad Virgen de las Nieves (Granada, España) y presentando signos de lesión hepática inducida por fármacos (DILI). Veinticuatro niños que recibían un tratamiento similar pero que no presentaban signos de DILI fueron seleccionados como grupo de control. RESULTADOS: Los niños con el KIR K2DS2 tenían cuatro veces más probabilidades de tener hepatotoxicidad (OR=4.08, P=0.034, IC del 95%: 1.1-15). Los pacientes con 2DS2 y el ligando C1 tenían diez veces más probabilidades de sufrir un episodio de hepatotoxicidad (P=0.007). CONCLUSIONES: Los KIRs pueden ser factores de riesgo para la susceptibilidad a la hepatotoxicidad tras la quimioterapia.Instituto de Salud Carlos II

Lesión hepática inducida por quimioterapia en niños.

Drug-induced liver injury due to chemotherapy is an important cause of morbidity in cancer patients, although its clinical manifestations are poorly understood. The objective of the present study was to determine the characteristics (forms of presentation, severity, and type of injury) of hepatotoxicity due to chemotherapy in children treated for cancer. A total of 22 oncological patients were included in the study, after ruling out other causes of increased transaminases (infectious, metabolic, autoimmune, or hereditary), according to the CIOMS causality scale, it is concluded that it was a possible, probable or definite episode of hepatic injury by drugs. All children had more than one episode of hepatotoxicity, and a total of 98 episodes are analysed. Methotrexate was the most commonly implicated drug. The histological pattern of predominant damage was hepatocellular. Only 2episodes were classified as serious. Idiosyncratic hepatotoxicity due to chemotherapy is frequent, with a tendency to relapse with re-exposure. Although it does not usually have important consequences, the high frequency makes it advisable to establish standardised safety algorithms with very strict monitoring of liver enzymes during high periods of risk in chemotherapy

Analysis of Immunogenetic Factors in Idiosyncratic Drug-induced Liver Injury in the Pediatric Population

Objetivos: La lesión hepática inducida por fármacos idiosincrásica es una enfermedad compleja multifactorial, en la que el potencial tóxico del fármaco, junto con factores genéticos y adquiridos y deficiencias en los procesos adaptativos, que limitan la extensión del daño, pueden determinar la susceptibilidad y hacer que los individuos sean únicos en su desarrollo de hepatotoxicidad. El objetivo del presente estudio es analizar los factores genéticos (antígeno leucocitario humano [HLA], polimorfismos de citocinas y genotipo del receptor tipo inmunoglobulina de células asesinas [KIR]) de niños que experimentan un episodio de lesión hepática inducida por fármacos. Pacientes y métodos: Estudio prospectivo multicéntrico de casos y controles. Los sujetos incluidos en el estudio fueron 30 pacientes pediátricos-infantes y niños de edades entre 0 y 15 años que presentaron una posible enfermedad hepática asociada con la ingesta de medicamentos, productos herbarios, drogas o toxinas. Como grupo de control, se seleccionaron 62 sujetos. Resultados: Aunque HLAC0401 y HLADQB0603 pueden proporcionar un mecanismo hepatoprotector en la población pediátrica, HLADQA0102 y HLA-DR*12 se encuentran más comúnmente en niños enfermos y su presencia puede estar relacionada con daño hepático. El inhibidor KIR KIR3DL1 no estaba presente en ningún niño del grupo de control. Conclusiones: Los polimorfismos que son bajos productores de interleucina-10 ocurren con mayor frecuencia en niños que han experimentado hepatotoxicidadInstituto de Salud Carlos II